Iontophoresis device and method of assembling the same

ABSTRACT

The present invention relates to an iontophoresis device, which can ensure the long-term stability of a drug and makes the operations for assemblage upon application easy as well as a method of assembling the device. A backing layer ( 4 ) is provided with a drug-dissolving portion ( 11 ) on a donor electrode-printed portion ( 6 ) thereof and a drug support ( 14 ) removably contacts with the drug-dissolving portion. A liner ( 12 ) is disposed on the backing layer on the skin ( 40 ) side and this is peeled off upon practical use. An opening ( 15 ) is formed on the liner ( 12 ) and an opening ( 5 ) is formed on an electrode portion (Ib). When assembling the device, these openings coincide with each other to thus easily and precisely dispose the drug support ( 14 ) on the drug-dissolving portion ( 11 ).

TECHNICAL FIELD

The present invention relates to an iontophoresis device suitable forpercutaneous and mucosal applications of drugs and in particular toiontophoresis device of the type, which is activated before practicallyusing as well as a method of assembling the same.

BACKGROUND ART

Recently, there have been developed a variety of dosage forms in thefield of pharmaceutical preparations for external use (externalpharmaceutical preparations) and the development has gradually become amatter of great concern. The reason for this is as follows: Theadministration of a drug, which may have a local or systemicpharmacological action, through the skin or the mucous membranes hasmany advantages. For instance, the sustained-release effect of the drugcan be expected; such administration is not greatly influenced by themetabolism due to the first-pass effect in the liver unlike the oraladministration and permits the effective use of the drug; and drugsaccompanied by, for instance, liver disorders can relatively safely beadministered.

However, the normal skin naturally has a protective effect againstexternal stimulations and this makes the absorption and penetration of adrug through the skin relatively difficult. For this reason, in theexisting circumstances, a drug is not absorbed in an amount sufficientfor ensuring a sufficient effect even if the drug is administered in adosage form for external use. Moreover, in the administration method,which makes use of absorption routes through biological membrane otherthan the skin, such as mouth, rectum, oral cavity and nose as well asthe sublingual route, it is difficult to penetrate into or transmitthrough the related biological membrane depending on the kind of drugsand therefore, there have been known a large number of drugs having lowbioavailability. Accordingly, there has been desired for the developmentof an absorption-promoting method, which can sufficiently enhance thepermeability, penetrability and absorbency of a drug against the skinand other biological membranes, can ensure a sufficient pharmacologicalefficacy of the drug and is substantially free of, for instance, itslocal and systemic toxicity and is highly useful and safe.

As such absorption-promoting methods, there have recently been known,chemically promoting methods, which make use of absorption-promotingagents, and physically promoting methods in which iontophoresis orphonophoresis is employed. Among them, the iontophoresis hasunexpectedly attracted special interest recently and has been expectedas an administration method, which can solve the foregoing problems.

The iontophoresis is a method for the administration of a drug byapplying a voltage to the skin or a mucous membrane to electricallyinduce the migration of an ionic drug and to thus administrate the drugthrough the skin or a mucous membrane. In general, an iontophoresisdevice is provided with a pair of electrodes for iontophoresis, i.e., ananode and a cathode and the device is so designed that these electrodesare arranged on or attached to the skin at a predetermined distanceapart from one another and an electric current generated by a currentgenerator is guided to these electrodes to thus carry out treatments.

Moreover, this iontophoresis device has a structure comprising acombination of these electrodes and a layer, which stores a drugtherein, and a variety of additives for maintaining the drug efficacyare optionally enclosed in the layer in addition to a predeterminedamount of the effective component in order to keep a desired bloodconcentration in the body over a long period of time.

The iontophoresis device of this type is, for instance, disclosed inJapanese Un-Examined Patent Publication Nos. Sho 62-268569, Hei2-131779,Hei3-268769 and Hei3-45271 and TOKUHYO Nos. Hei 3-504343 and Hei3-504813.

However, if a drug (such as physiologically active peptides), whichsuffers from a problem of the solubility in water, ,is used in theseiontophoresis device, the predetermined amount of the drug may bereduced due to the partial decomposition thereof with time. Moreover, ifthe drug is administered in a high concentration, the drug may bediluted during storing.

If a peptide drug is percutaneously administered by the iontophoresis,it is common that the drug is not maintained in an iso-electricenvironment, but is kept in an acidic or basic environment. For thisreason, the stability of additives, which are incorporated into thedevice to assist the development of the pharmacological efficacy of thebiologically active substance, is greatly influenced by such acidic orbasic environment and accordingly, the drug efficacy may be reduced.

Moreover, it has been recognized that when physiologically activepeptides are stored in the form of solutions, members constituting thepharmaceutical preparation may be adsorbed on the peripheral site and itis thus quite difficult to maintain a desired concentration of the drugover a long period of time.

As other problems, it has been reported that in a device, which isdesigned in such a manner that an electrically conductive layercontaining a drug in the form of a solution is directly in contact withthe electrodes immediately after the electrical charging, the drug iselectrolytically decomposed on the electrode surface during electricallycharging the device. Accordingly, it would be doubtful whether thedecomposed drug through its internal absorption adversely affects thehuman body.

There have been proposed a variety of methods for the solution of such aproblem. For instance, Japanese Un-Examined Patents Publication No. Sho63-102768 and U.S. Pat. No. 5,310,404 disclose a method, which comprisesthe steps of arranging a capsule or porch enclosing water or anelectrolyte solution above the electrode structure and breaking thecapsule or porch immediately before the practical use to thus impregnatethe drug-support layer therewith. This method is excellent in that thedrug can be stored in a stable condition (dry state), but it is stillinsufficient since it takes a long time for uniformly permeating themoisture into the whole drug-support layer and the drug efficacy may bereduced due to the dilution of the drug.

In addition, Japanese Patent No. 2,542,792 discloses a method in which adrug-support layer and an electrode layer containing an electrolyte areseparately disposed in distinct compartments, which are hinged to oneanother and then piling one upon another at the hinged portion to thusactivate the device. This method permits the improvement in thelong-term stability of a drug, but any means for activating the deviceupon application is not sufficiently devised and therefore, the methodmay include a lot of causes for artificial errors and cannot achievesufficiently uniform distribution of the drug after the activation ofthe device.

Moreover, Japanese Un-Examined Patent Publication No. Hei 3-94771discloses a device, which is so designed that a selective ion-permeablemembrane (such as an ion-exchange membrane) is arranged such that themembrane is adjacent to the skin side of a water-support portionthereof, while a drug is dried and adhered to the side of the selectiveion-permeable membrane, which is in contact with the living body, tothus prevent any dilution of the drug and to realize the administrationof a trace a mount of the drug to a local site in a high concentration.

Japanese Un-Examined Patent Publication No. Hei 9-201420 discloses adevice for iontophoresis, in which an electrode structure layer, asolvent-support layer and a drug-support layer containing a driedphysiologically active substance are put in a layer structure in thisorder and a water-impermeable separator layer is positioned between thesolvent-support layer and the drug-support layer. This device is sodesigned that the solvent-support layer is automatically brought intocontact with the drug-support layer by pulling out the separator layerupon activation. This device is quite excellent in that the occurrenceof any artificial error is prevented when assembling the device. In thisdevice, however, the solvent-support layer and the drug-support layerare accommodated in the same package, the stability of the drug may bereduced due to any leakage of the solvent from the solvent-support layerand accordingly, it is difficult to ensure the quality of the device.Moreover, even if it were technically possible to completely prevent theleakage of the solvent, the cost required for the development of such atechnique would be very high.

As has been described above, there has not yet been developed anyiontophoresis device, which can ensure the long-term stability of adrug, can easily and accurately be assembled immediately before thepractical use thereof and permits the elimination of any artificialerror as much as possible.

Accordingly, it is an object of the present invention to provide aniontophoresis device, which can ensure the long-term stability of a drugand can easily be assembled immediately before the application as wellas a method of assembling the device.

Disclosure of the Invention

The foregoing object of the present invention can be accomplished byproviding an iontophoresis device, in which an electrode portionequipped with a drug-dissolving portion and a drug portion equipped witha drug-support are provided with alignment structures respectively sothat the drug-support and the drug-dissolving portion are brought intocontact with one another by coinciding the alignment structure of thedrug portions with that of the electrode portion. These alignmentstructures are, for instance, openings formed on the electrode portionand the drug portion, respectively. These portions can accurately andrapidly be aligned by aligning these openings of the electrode and drugportions with one another.

In addition, the device is also designed in such a manner that anelectric current-supply portion is provided with the same alignmentstructure, the alignment structure is coincided with that of theelectrode portion to thus contact the current-supply portion with theelectrode portion. The alignment structure for the current-supplyportion may be an electrode terminal. In this case, the alignmentstructure may be formed on the terminal connected to the current-supplyportion through a connecting cord.

Alternatively, a connector having the same alignment structure isdisposed and the alignment structures of every portions are coincidedwith one another to thus connect them to the current-supply portion andthe connector through the electrode portion. If some of these alignmentstructures are formed from an electrically conductive material, suchalignment structures may be used as electrical connection means.

The drug portion of this iontophoresis device is stored as a packageseparated from the parts such as those for the current-supply andelectrode portions, prior to the practical use. Thus, the device isdesigned such that the electrode and drug portions are mechanicallyconnected or the electrode and current-supply portions are electricallyconnected to one another. A means for holding this arrangement usedherein is, for instance, electrode terminals of the current-supplyportion or conductive snap connector or an auxiliary stand forassemblage. As has been described above, the device according to thepresent invention may be a set of units in which the electrode portionequipped with an alignment structure and the drug portion equipped withthe same alignment structure are separately packaged. In addition, thecurrent-supply portion or the connector having an identical alignmentstructure and an auxiliary stand for alignment are also packagedseparately from the drug portion, in this set of units.

The electrode portion (electrode unit) used herein comprises a memberholding a conductive layer, a wiring connected to the conductive layerand an alignment structure formed on at least one of the wiring and themember. The alignment structure is an opening formed on at least one ofthe wiring and the member. On the other hand, the drug portion (drugunit) comprises a drug-support, a peelable cover for protecting thedrug-support and an alignment structure formed on the cover. In thiscase, the alignment structure is an opening formed on the edge of thecover.

The method of assembling the iontophoresis device according to thepresent invention comprises the steps of peeling off a cover materialdisposed on an electrode portion; coinciding an alignment structure ofthe electrode portion with that of a drug portion to thus dispose adrug-support of the drug portion on a drug-dissolving portion; peelingoff a cover of the drug-support on the side of the drug-dissolvingportion; and fixing the drug-support to the electrode portion. In thisdevice, a cover is also positioned on the drug-support opposite to theside of the drug-dissolving portion. In this case, however, if anopening is formed on the cover, the assemblage of this device can becompleted without peeling off the cover. On the other hand, if anyopening is not formed on the opposite cover, the assemblage of thedevice is completed after peeling off at least part of the cover. Morespecifically, the opposite cover may completely be peeled off or thepart of the cover other than the portion provided with the alignmentstructure may, for instance, be peeled off.

The electrode portion and the drug portion can be aligned with oneanother, while making use of the alignment structure disposed on anauxiliary stand, a current-generating portion or a connector. In thiscase, the both alignment structures of the electrode and drug portionsare constituted by openings, while the alignment structure of theauxiliary stand is constituted by an alignment rod capable of beinginserted into the opening. On the other hand, the alignment structuresfor the current-generating portion and the connector may be electrodeterminals thereof.

Thus, an iontophoresis device and a method of assembling the same can beprovided, which can ensure the long-term stability of a drug, whoseassembling operations are easy and accurate upon application and whichcan eliminate any cause of artificial errors as much as possible.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing the cross sectional structure of aniontophoresis device according to the present invention, immediatelybefore the practical use.

FIG. 2 is a diagram showing an embodiment of a drug portion (drug unit),wherein (a), (b) and (c) are a view of the surface, an internal view anda cross sectional view of the drug unit, respectively.

FIG. 3 is a diagram illustrating an embodiment of the structure of acurrent-generating portion Ia, in which (a), (b) and (c) are a view ofthe surface, a view of the back face and a cross sectional view of thecurrent-generating portion, respectively.

FIG. 4 is a diagram illustrating an embodiment of the structure of anintegrated electrode portion (electrode unit) Ib-1, in which (a), (b),(c) and (d) are a view of the surface, an internal view, a view of theback face and a cross sectional view of the electrode portion,respectively.

FIG. 5 is a diagram showing an embodiment of the structure of a separatetype electrode portion (electrode unit) Ib-2, in which (a), (b) and (c)are a view of the surface, an inner view and a view of the back face ofthe electrode portion, respectively.

FIG. 6 is a diagram showing an embodiment of the structure of aconductive snap connector Id, in which (a) and (b) are a view of thesurface and a cross sectional view thereof, respectively.

FIG. 7 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-1, wherein (a) and (b) are a view ofthe surface and a cross sectional view, respectively.

FIG. 8 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-2, wherein (a) and (b) are a view ofthe surface and a cross sectional view, respectively.

FIG. 9 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-3, wherein (a) and (b) are a view ofthe surface and a cross sectional view, respectively.

FIG. 10 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-4, wherein (a) and (b) are a view ofthe surface and a cross sectional view, respectively.

FIG. 11 is a diagram showing the configuration of an iontophoresisdevice in which the integrated electrode portion Ib-1 is incorporatedaccording to the present invention after the completion of itsassemblage, wherein (a) and (b) are a view of the surface and a view ofthe back face of the device, respectively.

FIG. 12 is a diagram showing the configuration of an iontophoresisdevice in which the separate type electrode portion Ib-2 is incorporatedaccording to the present invention after the completion of itsassemblage, wherein (a) and (b) are a view of the surface and a view ofthe back face of the device, respectively.

FIG. 13 is a diagram showing an embodiment in which thecurrent-generating portion Ia is connected to the electrode portionthrough a connecting line 30, wherein (a), (b) and (c) are a connectingcord, a view of the surface and a view of the back face, respectively.

FIG. 14 is a diagram illustrating an embodiment of the method ofassembling an iontophoresis device, which makes use of an integratedelectrode, in which (a) shows assembling processes and (b) shows aprocess in which the auxiliary stand Ie-4 for assemblage is used.

FIG. 15 is a diagram illustrating another embodiment of the method ofassembling an iontophoresis device, which makes use of an integratedelectrode, in which (a) shows the first half of the assembling processand (b) shows the second half of the process, respectively.

FIG. 16 is a diagram illustrating a further embodiment of the method ofassembling an iontophoresis device, which makes use of an integratedelectrode, in which (a) shows the first half of the assembling processand (b) shows the second half of the process, respectively.

FIG. 17 is a diagram illustrating an embodiment of the method ofassembling an iontophoresis device, which makes use of a separate typeelectrode, in which (a) shows the first half of the assembling processand (b) shows the second half of the process, respectively.

FIG. 18 is a schematic diagram showing an iontophoresis device as acomparative example, in which (a), (b) and (c) are a view of thesurface, views of the inner portion and back face and a cross sectionalview of the device, respectively.

FIG. 19 is a graph showing changes, with time, of salmon calcitonin inthe serum observed in Test Example 1.

FIG. 20 is a graph showing changes, with time, of the rate of the salmoncalcitonin remaining in the drug portion, observed in Test Example 2.

BEST MODE FOR CARRYING OUT THE INVENTION

FIG. 1 is a diagram showing the cross sectional structure of aniontophoresis device according to the present invention, immediatelybefore the practical use. In this figure, every parts are depictedseparately to make, easier, the understanding of these parts which arein fact in a laminated relation or come in close contact with oneanother.

In this figure, a donor electrode-printed portion 6 is positioned on oneside of a backing layer 4 and a reference electrode-printed portion 7 ispositioned on the other side of the layer 4. An adhesive film 3 such asa medical adhesive tape is disposed on the periphery of the backinglayer 4 for securing a pharmaceutical preparation to an applicationsite. The both electrode-printed portions 6 and 7 are connected to acurrent-generating portion Ia through a conductive snap connector Id.The donor electrode-printed portion 6 on the backing layer 4 is providedwith a conductive layer 10 (a drug-dissolving portion) on the donorelectrode side, while the reference electrode-printed portion 7 isprovided with a conductive layer 10 on the reference electrode side. Adrug-support 14 is removably connected to the drug-dissolving portion11. An adhesive layer 13 is formed on the periphery of the drug-support14. Thus, the drug-support 14 is fixed to the backing layer 4 or thedonor electrode-printed portion 6 through the peripheral adhesive layer13. On the other hand, a liner 12 is disposed on the peripheral adhesivelayer 13 and on the side facing the skin 40.

The liner 12 is peeled off from the iontophoresis device having such astructure upon the practical use and thus the drug-support 14 isexposed. The device, which is in such a condition, is applied to theskin 40. At this stage, the drug, which is in a dry state and supportedby the drug-support 14, is dissolved in the water supplied from thedrug-dissolving portion 11. Then a power supply for thecurrent-generating portion Ia is switched on to thus put theiontophoresis device in operation.

In this respect, the liner 12 is provided with an opening 15 as a firstalignment structure. Moreover, the electrode portion Ib is also providedwith an opening 5 as a second alignment structure. In the application ofthe device, the drug-support 14 can easily and accurately be positionedon the drug-dissolving portion 11 by aligning these openings with oneanother. At this stage, an electrode terminal of the current-generationportion Ia as a third alignment structure or the connector Id as a fifthalignment structure is inserted into the opening to thus permit rapidpositioning operations.

Examples of structures of each part of such an iontophoresis device willbe described in more detail below.

FIG. 2 is a diagram showing an embodiment of a drug portion (or drugunit), wherein (a), (b) and (c) are a view of the surface, an internalview and a cross sectional view of the drug unit, respectively. The drugunit Ic of this example is formed by sandwiching a porous drug-support14 in between a liner 17 on the electrode side, serving as a protectivecover, and a liner 12 on the skin side. The liner 17 on the electrodeside is provided with a perforation 24 for folding the liner, while theliner 12 on the skin side is provided with two insertion openings 15 forconductive snap connectors as will be detailed below and a perforation16 for pulling out the liner after the completion of the assemblage.Both of these liners are formed from a film having a low adsorptiveaffinity for the drug such as polyethylene terephthalate. Moreover, thedrug is adhered to and supported on the drug-support 14 by means of, forinstance, spray coating or impregnation and then dried. Adhesive layers13 are arranged on the both sides and the periphery of the drug-support14 for the purpose of adhesion thereof to the electrode portion and theskin. The adhesive layer 13 is coated on the support in a stripe-likepattern for ensuring ventilation. In this connection, the liners 12 and17 are subjected to a silicone treatment on the side, which comes incontact with the drug-support 14 in order to prevent any adsorption ofthe drug and to improve the releasability thereof. Further the linersmay likewise be subjected to a treatment for inhibiting any diffusion ofa drug solution to the peripheral adhesive layer 13.

Then materials or the like for each part of the drug unit will bedescribed below. The peripheral adhesive layer 13 for the drug-supportcan be formed by the use of an adhesive as will be detailed below inconnection with an adhesive film 3. This layer is formed by patterncoating (such as intermittent coating, stripe coating, intermittentstripe coating) and desirably has a structure through which the aireasily passes. The width of the pattern coating is not restricted to anyparticular one insofar as they can ensure good balance between theadhesion and the air permeability, but the width desirably ranges from0.1 mm to 20 mm.

The drug-support 14 may be any one insofar as it can support a drugconsisting of a physiologically active substance and permits thepermeation of the drug therethrough. Moreover, if the drug is aphysiologically active peptide or a protein, a hydrophilic porousmaterial may be used, which can support dried drugs and has lowadsorptivity. The hydrophilic film formed from such a hydrophilic porousmaterial includes a thin film having high wettability by water such as ahydrophilized hydrophobic (or water-repellent) polymer thin film or ahydrophilic substance-containing hydrophilic polymer film.

Examples of hydrophilized hydrophobic polymer thin films are thin filmsformed from hydrophilized fluoroplastics (such as hydrophilic DURAPOREavailable from Millipore Company and hydrophilicpoly(tetrafluoroethylene) available from Toyo Roshi Co., Ltd.), thinfilms such as those formed from hydrophilic polyther sulfone (such asSupor available from Gelman Sciences Inc.) and hydrophilized cellulosederivatives (such as hydrophilized cellulose monoacetate andhydrophilized cellulose triacetate).

Examples of hydrophilic substance-containing hydrophilic polymer thinfilms include a variety of polymers obtained by adding appropriatesurfactants and impregnating therewith and then drying, for instance,hydrophilized cellulose acetate films (such as Asymmetric Ultra Filteravailable from sartorius Company and cellulose acetate type onesavailable from Toyo Roshi Co., Ltd.), hydrophilized polycarbonate films(such as Isopore Membranes available from Nihon Millipore Ltd.),hydrophilized poly (tetrafluoroethylene) films (such as OmniporeMembranes available from Nihon Millipore Ltd.), hydrophilizedpolysulfone films (such as HT Tuffryn available from Gelman SciencesInc.) and hydrophilized nonwoven fabrics (such as films obtained bycoating polyester nonwoven fabrics with cellulose acetate (e.g., coatedtype membranes available from Toyo Roshi Co., Ltd.)). The hydrophilicfilms also include, for instance, nylon films (such as Biodyne availablefrom Nihon PALL Ltd.).

Incidentally, drugs unstable to water should desirably be included in oradhered to the drug-support in their dried state in order to improve thestability of these drugs and to inhibit any leakage and deteriorationthereof. On the other hand, in case of drugs stable to water, they maybe supported on the drug-support in their gel-like conditions. In such agel-like drug-support, suitably used are water-soluble polymers andhydrogel thereof. A method for preparing such a gel-like drug-supportcomprises the step of mixing and kneading a gelling agent such as awater-soluble polymer and a drug solution. Moreover, the electricalconductivity of the gel-like drug-support can be enhanced by addition ofan electrolyte such as sodium chloride, potassium chloride, sodiumcarbonate, phosphoric acid or sodium citrate; or a pH-buffering agentsuch as acetic acid, sodium acetate, phosphoric acid, sodium phosphate,citric acid or sodium citrate. Moreover, the kneaded mixture is formedinto a product to such an extent that it has a selfshape-maintainability and then spreaded into a sheet or a film. If thekneaded mixture has an insufficient self shape-maintainability, amesh-like support may be introduced into the gel. The thickness of thegel layer desirably ranges from 0.1 to 2 mm and particularly preferably0.3 to 0.8 mm. If it is too thin, the gel strength is considerably low,while if it is too thick, the movement of the drug is inhibited andaccordingly, the rate of drug absorption is reduced.

The liners 12, 17 as the protective members may be any one insofar asthey are formed from a water-impermeable material, but are desirablythose capable of being processed through molding (such as thermalmolding and vacuum forming). Examples of such water-impermeablematerials usable herein are aluminum foils, polyester films,polypropylene films and polyethylene films as well as laminated filmsthereof. In addition, it is desirable to use these materials aftersubjecting them to an adsorption-inhibitory treatment such as atreatment with silicone or Teflon. This treatment would facilitate thepeeling off thereof from the adhesive layer.

Drugs usable herein are any medicine used in any therapeutic field,which is soluble or dispersible in water and, in particular,physiologically active substances having a molecular weight ranging from1×10² to 1×10⁶ can widely be used. Examples of drugs are narcotics,analgesics, anorexics, anthelmintics, drugs for asthma, anticonvulsants,antidiarrheals, antineoplastic agents, drugs for Parkinson's disease,antipruritics, sympatholytic agents, xanthine derivatives, drugs forangiocardiac diseases such as calcium channel blockers, antipyretics,β-blockers, antiarrhythmic agents, hypotensive drugs, diuretics,vasodilators for blood vessels including systemic, coronary, peripheraland cerebral vessels, drugs for hemicrania, drugs for drunkness andmotion sickness, antiemetics, central nervous system stimulants, drugsfor cough and common cold, decogestants, diagnostics, drugs forhormonotherapy, parasympatholytic agents, parasympathomimetic agents,psychostimulants, sedatives, tranquilizers, anti-inflammatory agents,anti-arthritic agents, anti-spasmodics, antidepressants, drugs fortreating psychosis, drugs for treating dizziness, anti-anxiety agents,narcotic antagonists, carcinostatic agents, hypnotics,immunosuppressors, muscle relaxants, antiviral agents, antibiotics,anorexics, antiemetics, anti-cholinergic agents, antihistamic agents,contraceptives, antithrombotic agents, bone-absorption suppressors andosteogenesis-promoting agents. However, the present invention is notrestricted to these specific drugs. These drugs may be used alone or inany combination.

Specific examples of these drugs include steroids such as estradiol,progesterone, norgestrel, levonorgestrel, norethindrone,medroxy-progesterone acetate, testosterone and esters thereof; nitrogroup-containing compounds and derivatives such as nitroglycerin andisosorbide dinitrates, nicotine, chlorpheniramine, terfenadine,triprolidine and hydrocortisone; oxicam derivatives such as piroxicam;acetic acid or propionic acid derivatives such as indometacin,flurbiprofen, felbinac and diclofenac, ketoprofen; mucopolysaccharidasessuch asrthiomucase, buprenorphine, fentanyl, naloxone, codeine,lidocaine, dihydroergotamine, pizotyline, salbutamol and terbutaline;prostaglandins such as misoprostol, enprostil, omeprazole andimipramine; benzamides such as metoclopramine, scopolamine andclonidine; dihydropyridines such as nifedipine, verapamil, ephedrine,pindolol, metoprolol, spironolactone, nicardipine HCl and calcitriol;thiazides such as hydrochilorothiazide and flunarizine; sydnone iminessuch as molsidomine; sulfated polysaccharides such as heparin fractionsand proteins; and peptides such as insulin and homologues thereof;calcitonins and homologues such as elcatonin, protamin and glucagone;globulins, angiotensin I, angiotensin II, angiotensin III, lypressin,vasopressin, somatostatin and homologues thereof; growth hormones andoxytocin; as well as, if necessary, pharmaceutically acceptable saltsthereof with acids or bases. Preferred are, for instance, narcotics,hormones, proteins, analgesics, or other low molecular weight cations.More preferably, examples of drugs include peptides or polypeptides suchas insulin, calcitonin, calcitonin-related genetic peptides,vasopressin, desmopressin, protirelin (TRH), adrenocorticotropichormones (ACTH), luteinizing hormone-release hormones (LH-RH), growthhormone-release hormone (GRH), nerve growth factors (NGF) and otherrelease factors, angiotensins, parathyroid hormone (PTH), luteinizinghormone (LH), serumal gonadotropin, hypophyseal hormones (such as HGH,HMG, HCG), growth hormones, somatostatin, somatomedin, glucagon,oxytocin, gastrin, secretin, endorphin, enkephalin, endothelin,cholecystokinin, neurotensin, interferon, interleukin, transferrin,erythropoietin, superoxide dismutase (SOD), filgrastim (G-CSF),vasoactive-intestinal-polypeptides (VIP), muramyl dipeptides,corticotropin, urogastrone and atrial sodium uragogue peptides (h-ANP).However, the present invention is not restricted to these specificdrugs. Among these, particularly preferred are peptide hormones. It isalso possible to optionally use adsorption-inhibitory agents such asbenzalkonium chloride, BSA (bovine serum albumin) and monolauric acid.

In the present invention, at least one of the foregoing drugs and saltsthereof may be supported on the drug-support. In addition, the amount ofthe drug is determined depending on a particular drug in such a mannerthat upon administration thereof to a patient, a predetermined effectiveblood concentration is maintained over an effective period of time andthe size of the iontophoresis device as well as the area of thedrug-delivery surface thereof are determined in proportion thereto.

FIG. 3 is a diagram illustrating an embodiment of the structure of acurrent-generating portion Ia, in which (a), (b) and (c) are a view ofthe surface, a view of the back face and a cross sectional view of thecurrent-generating portion, respectively. The current-generating portionIa is a plastic molded body having therein a built-in current-controlcircuit. A current-control switch 1 is arranged on thecurrent-generating portion, while a female or male electrode terminal 2(one each of the terminal on the sides of the anode and cathode) isarranged below the current-generating portion. This current-generatingportion Ia is preferably designed such that no physical burden due tothe size and weight thereof is given to a patient.

More specifically, the current-generating portion is constituted by aself-oscillator circuit provided with a built-in small-sized cell, anappropriate high voltage-generating circuit connected to the oscillatorcircuit and a control circuit for operating and controlling thesecircuits. It is also possible to incorporate a BOLUS button fortemporarily increasing the injection rate for a drug into thecurrent-generating portion. This is quite useful function when ananalgesic is administered to a patient and the patient desires for atemporary increase in the dose thereof in proportion to the degree ofhis pains.

Moreover, the control circuit is, for instance, designed in such amanner that the circuit permits the manual on/off switching in order toallow the on-demand medication regime and the on/off switching at aperiod adapted for the biological circadian rhythm and the pattern atintervals of 24 hours. In addition, the control circuit may be equippedwith a built-in microprocessor and therefore, the circuit permits themodification of the level of the current and the wave form such aspulses and sinusoidal waves to be applied over a predetermined time.Moreover, the control circuit may comprise a biosensor or a certain kindof feedback system for monitoring the biosignals of a patient,evaluating the treating method and adjusting the amount of the drug tobe administered to the patient in response to the results of theevaluation. It is also possible to incorporate one or more programspredetermined by the maker of the drug, a physician or a patient intothe control circuit.

FIG. 4 is a diagram illustrating an embodiment of the structure of anintegrated electrode portion Ib-1, in which (a), (b), (c) and (d) are aview of the surface, an internal view, a view of the back face and across sectional view of the electrode portion, respectively. Theintegrated electrode portion Ib-1 has a backing layer 4 consisting of afilm of a polyolefin such as polyester or polypropylene or a molded bodyof such a film laminated with an aluminum layer. Printed electrodeportions 6, 7 are arranged on the molded backing layer 4 and they areformed by printing silver (on the anode side) and silver chloride (onthe cathode side). Moreover, two insertion openings 5 (one each of theopening on the sides of the anode and cathode) for conductive snapconnectors are positioned on the printed electrode portion at the centerof the backing layer.

Conductive layers 10, 11 are formed on the integrated electrode portionIb-1 in such a manner that they are adjacent to the printed electrodeportions 6, 7 and the material used for forming these layers is awater-retentive material such as a nonwoven fabric or a hydrophilicpolymer, which comprises an electrolyte. In this respect, the conductivelayer 11 on the donor side (in this example, the layer on the anodeside) also serves as a moisture supply source for the drug accommodatedin the drug portion Ic upon activation. Moreover, the conductive layersare packaged with a water-impermeable cover material 9 through easilypeeled heat seal in order to prevent any moisture evaporation duringstorage. Further an adhesive film 3 such as a medical adhesive tape isapplied onto the periphery of the backing layer 4 for the purpose offixing the pharmaceutical preparation to a drug-application site and aliner 8 is fitted to the adhesive film during storage.

FIG. 5 is a diagram showing an embodiment of the structure of a separatetype electrode portion Ib-2, in which (a), (b) and (c) are a view of thesurface, an internal view and a view of the back face of the electrodeportion, respectively. The separate type electrode portion Ib-2 has abacking layer 4 consisting of a film of a polyolefin such as polyesteror polypropylene or a molded body of such a film laminated with analuminum layer. Printed electrode portions 6, 7 are arranged on themolded backing layer 4 and they are formed by printing silver (ion theanode side) and silver chloride (on the cathode side). Moreover, aninsertion opening 5 for each conductive snap connector is positioned onthe printed electrode portion 6, 7.

Conductive layers 10, 11 are formed on the separate type electrodeportion Ib-2 in such a manner that they are adjacent to the printedelectrode portions 6, 7 and the material used for forming these layersis a water-retentive material such as a nonwoven fabric or a hydrophilicpolymer, which comprises an electrolyte. In this respect, the conductivelayer 11 on the donor side (in this example, the layer on the anodeside) also serves as a moisture supply source for the drug accommodatedin the drug portion Ic upon activation. Moreover, the conductive layersare packaged with a water-impermeable cover material 9 through easilypeeled heat seal in order to prevent any moisture evaporation duringstorage. Further an adhesive film 3 such as a medical adhesive tape isapplied onto the periphery of the backing layer 4 for the purpose offixing the pharmaceutical preparation to a drug-application site and aliner 8 is fitted to the adhesive film during storage.

Incidentally, these electrode portions may have a known electrodestructure. For instance, usable herein are materials such as platinumblack, titanium, carbon, aluminum, iron, lead, carbon-containingconductive rubber and conductive resins, with platinum electrodes,silver electrodes, silver chloride electrodes or the like beingparticularly desirable.

In addition, the cover material 9 is not restricted to any particularone insofar as it is formed from a water-impermeable material. Forinstance, the cover material is formed from a film laminated with analuminum layer. If a highly sealed condition by heat sealing isrequired, the cover material is laminated with a plurality of films suchas those described above in connection with the liner or it is coatedwith another polymer resin. This makes the peeling off of the covermaterial easy. For instance, there can be used an easily peelablelaminate film. It is desirable that the laminate film have a peelstrength at 180 degrees of not more than 2000 g.

A pressure-sensitive adhesive is used as an adhesive material for theadhesive film 3 (the adhesive layer 13 at the periphery of the drugsupport). Any pressure-sensitive adhesive maybe used herein insofar asthey can maintain the iontophoresis device on the surface of the skin ormucous membrane of a patient, while the device is brought into closecontact therewith, they have an adhesive force sufficient for ensuringgood adhesion of the drug support to the drug-dissolving portion andthey are physiologically acceptable for the skin. Specific examplesthereof are acrylic adhesives comprising homopolymers or copolymers ofalkyl acrylates whose alkyl moiety has 4 to 18 carbon atoms, such asacrylic acid, methyl acrylate, ethyl acrylate, 2-ethylhexyl acrylate,isooctyl acrylate, decyl acrylate, lauryl acrylate and stearyl acrylate;methacrylic adhesives comprising homopolymers or copolymers of alkylmethacrylates whose alkyl moiety has 4 to 18 carbon atoms, such asmethyl methacrylate, ethyl methacrylate, butyl methacrylate,2-ethylbexyl methacrylate, isooctyl methacrylate, decyl methacrylate,lauryl methacrylate and stearyl methacrylate; silicone, type adhesivessuch as those comprising polyorganosiloxane and polydimethyl-siloxane;and rubber type adhesives such as those comprising natural rubber,polyisobutylene, polyvinyl ether, polyurethane, polyisobutylene,polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymerand styrene-isoprene-styrene block copolymer. Moreover, the adhesivematerial may, if necessary, comprise a tackifier and a softening agent.

A material for the backing layer 4 herein used may be an effectivecomponent-impermeable material. Examples thereof are films, sheets andfoams of synthetic resins such as polyethylene, polypropylene,polyethylene terephthalate, polyvinyl chloride, polyvinylidene chloride,plasticized vinyl acetate copolymer, plasticized vinyl acetate-vinylchloride copolymer, polyamide, cellophane, cellulose acetate, ethylcellulose, polyester, polycarbonate, polystyrene, polyurethane,polybutadiene, polyimide, poly-acrylonitrile, polyisoprene, polystyrenederivatives, ethylene-vinyl acetate copolymer, ethylene-polyvinylalcohol copolymer, fluoroplastics, acrylic resins, epoxy resins, whichmay be used alone or in the form of a laminate of at least two of them.

In addition, the films, sheets, foams or the like of these syntheticresins may be laminated with metal foils such as aluminum and tin foils;nonwoven fabrics and synthetic paper or may be covered with depositedaluminum layers and ceramic coatings. Moreover, if closed package by,for instance, heat sealing is required, they may be laminated with aheat-sealable material.

The electrode portion may be deposited on the backing layer by, forinstance, a method comprising the steps of mixing an electrode materialwith, for instance, a print ink for electric wirings, applying the printink to a material for the backing layer and then drying the same; amethod comprising the steps of spreading an electrode material and thenfixing the material to the backing layer; a method comprising the stepof depositing an electrode material onto the backing layer; or a methodin which the electrode portion is formed by photo-etching an electrodematerial applied onto the backing layer. In addition, an insulatinglayer may additionally be applied onto a part of the printed electrodelayer, which may come in contact with the skin of a patient.

The conductive layer may simply comprise water or may comprise at leastone member selected from the group consisting of soft porous materialssuch as ion-exchangeable polymers, foaming materials and sponge andwater-absorptive polymers. Moreover, the conductive layer may comprisean electrolyte such as sodium chloride, potassium chloride, sodiumcarbonate, phosphoric acid or sodium citrate; or a pH-buffering agentsuch as acetic acid, sodium acetate, phosphoric acid, sodium phosphate,citric acid or sodium citrate, for the improvement of the electricconductivity thereof.

Specific examples of the preferably used conductive layer in generalinclude nonwoven fabric, paper, gauze, absorbent wadding, polyethyleneor polypropylene having open cells, polyvinyl acetate, porous films andfoams of, for instance, polyolefin foams, polyamide foams andpolyurethane, natural polysaccharides such as karaya gum, tragacanthgum, xanthane gum, starches, gum arabic, locust bean gum, gellan gum,guar gum and carrageenan; gelatin, pectin, agar, sodium alginate orpolyvinyl alcohol and partially saponified products thereof; polyvinylformal, polyvinyl methyl ether and copolymers thereof; polyvinylpyrrolidone and copolymers thereof; aqueous or water-soluble cellulosederivatives such as sodium carboxymethyl cellulose, methyl cellulose,hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and cellulose acetate phthalate;carboxyvinyl polymer, polyacrylamide and polyacrylamide derivatives,casein, albumin, chitin, chitosan, polyacrylic acid, sodiumpolyacrylate, poly-HEMA, poly-HEMA derivatives, methoxyethylene-maleicanhydride copolymer, N-vinyl acetamide, N-vinyl acetamide and acrylicacid and/or acrylic acid salt copolymers, as well as crosslinkedproducts thereof, water-soluble polymers optionally plasticized with,for instance, ethylene glycol or glycerin and hydrogels thereof.However, the present invention is not restricted to these specific ones.In addition, the foregoing materials may be used in combination of atleast two of them. Moreover, it is also possible to use, if necessary,benzalkonium chloride, BSA (bovine serum albumin) andadsorption-inhibitory agent such as monolauric acid.

Furthermore, the conductive layer may also comprise an ion-exchangeablepolymer for the removal of ions competitive with a desired drug. Such anion-exchangeable polymer usable herein is appropriately selected fromanion-exchange polymer, cation-exchange polymer or ampholyticion-exchange polymer, depending on the ionic properties of eachparticular drug. In addition, the ion-exchangeable polymer may beincorporated into the conductive layer by, for instance, a methodcomprising the step of dispersing fine powder of an ion-exchangeablepolymer in the foregoing polymer to thus form the mixture in a gel-likeform or a method, which makes use of a product of such anion-exchlangeable polymer previously formed into a film, but the presentinvention is not restricted to these methods at all.

The capacity of the conductive layer on the donor electrode side(drug-dissolving portion) is not particularly restricted to a specificrange, but depends on, for instance, the size of the electrode portionand the optimum amount of water required for dissolving a drugaccommodated in the drug portion, or the water content of the absorptivemember of the drug-dissolving portion. In this respect, however, if theamount of water is too large, it may cause leakage of thedrug-dissolving liquid, while if it is too small, the drug present inthe drug portion cannot completely be dissolved and the drug efficacy iscorrespondingly reduced. Therefore, the amount of water is desirably onthe order of the maximum water absorption of the drug support. If ahydrogel is used in the drug-dissolving portion, the syneresis thereofparticularly preferably ranges from 10 to 100 mg/cm². Moreover, thehydrogel should have such a gel strength that the gel is never brokenduring the assemblage of the device and during the application thereofto the skin and therefore, the hydrogel desirably has a gel strengthranging from 400 to 1500 g/cm².

The amount of water required for dissolving a drug present in the drugsupport is in advance controlled in the drug-dissolving portion. Thus, aprecise amount of water can certainly and rapidly be supplied to thedrug support at any time upon practical use and this makes thetherapeutic effect accurate. Moreover, this can also simplify thetreating operations and reduce the treating time.

FIG. 6 is a diagram showing an embodiment of the structure of aconductive snap connector Id, in which (a) and (b) are a view; of thesurface and a cross sectional view thereof, respectively. This connectorId is provided with two electrode terminals 19 (male and female) on anelectrode terminal-fixing table 18 and they are designed in such amanner that they can be connected to the electrode terminals 2 (femaleand male) of the current-generating portion Ia after the assemblage ofthe device.

The current-generating portion Ia is connected to the electrode portionIb such that the latter is sandwiched between the electrode terminal onthe side of the current-generating portion and that on the side of theconductive snap connector Id. The electrode terminal on the conductivesnap connector side comes in contact with the printed electrode portion(either of the anode and cathode) of the electrode portion due to theconnection. Accordingly, the current-generating portion and theelectrode portion can electrically be charged and the electricalconnection can thus be established.

In addition, if they are connected, while inserting the drug portionupon the assemblage of the device, the electrode terminal also serves asa means for mechanical connection for the purpose of positioning oraligning the electrode portion with the drug portion. Thus, theelectrode terminals of the current-generating portion and the conductivesnap connector are important as means for assembling the device.

In respect of the modes of the connection of the current-generatingportion to the electrode portion, the device may be operated in acordless mode or a remote control mode using a cord. In case of theformer, a small-sized current-generating portion is directly connectedto the electrode portion when it is intended to carry out an easy andquick treatment. Besides, in case of the latter, the current-generatingportion is connected to the electrode portion through an exclusiveconnecting cord when it is intended to carry out a treatment whileoperating the device at hand. In this connection, connection means arefitted to the both sides of the connecting cord for connecting thecurrent-generating portion to the conductive snap connector.

In this embodiment, electrode terminals (both anode and cathodeterminals) are incorporated into a plastic molded body so that it servesto connect the terminals, to each other, of the current-generatingportion and the conductive snap connector. In this respect, theconnection means is not restricted to an electrode terminal and theshape and the connection mode thereof may arbitrarily be changed.Preferably, the connection means on the conductive snap connector sidehas such a structure that the drug portion and the electrode portion arein line with each other and they can firmly maintain a desiredarrangement.

FIG. 7 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-1, wherein (a) and (b) are a view ofthe surface and a cross sectional view, respectively. The auxiliarystand for assemblage Ie-1 is designed in such a manner that it possessesa space 21 for accommodating the electrode portion, whose shapecorresponds to that of the backing layer 4 of the electrode portion andthat it has two rods 20 as a sixth alignment structure used forpositioning upon the assemblage of the device. Materials for theauxiliary stand for assemblage are not restricted to any specific oneinsofar as they are those capable of being shaped and/or processed suchas paper, metals, wood and plastic films (such as polypropylene, Teflonand polyvinyl chloride films), but preferred are plastic films havinghigh shape-retention ability and a thickness of not less than 0.5 mm.

This auxiliary stand for assemblage is devised to make, easy, theoperations required when a patient assemble this device. In thisembodiment, the stand is provided with a space 21 for accommodating theelectrode portion, whose shape corresponds to that of the backing layer4 of the electrode portion and therefore, the electrode portion can bedisposed on the precise position on the auxiliary stand. Theelectrode-accommodating space 21 is also important in that it canprevent any damage of the electrode portion possibly encountered whenthe device is assembled.

In addition, the alignment rod 20 makes it easy to align the electrodeportion with the drug portion upon the assemblage of the device and iseffective for eliminating the occurrence of any artificial error.

FIG. 8 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-2, wherein (a) and (b) are a view ofthe surface and a cross sectional view, respectively. The auxiliarystand for assemblage Ie-2 is designed so as to have a space 23 foraccommodating the current-generating portion, whose shape is inconformity with that of the current-generating portion Ia. The space 23is provided with a means 22 for fixing the current-generating portion tothe auxiliary stand Ie-2.

FIG. 9 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-3, wherein (a) and (b) are a view ofthe surface and across sectional view, respectively. The auxiliary standfor assemblage Ie-3 is designed so as to have a space 23 foraccommodating the current-generating portion, whose shape is inconformity with that of the current-generating portion Ia and twoalignment rods 20. The functions of the alignment rods 20 and the space23 are the same as those discussed above in connection with theforegoing auxiliary stand.

FIG. 10 is a diagram showing an embodiment of the structure of anauxiliary stand for assemblage Ie-4, wherein (a) and (b) are a view ofthe surface and across sectional view, respectively. The auxiliary standfor assemblage Ie-4 is provided with a space 23′ for accommodating theconductive snap connector Id, whose shape is adapted for that of theconnector. The function of the space 23′ is the same as that describedabove in connection with the foregoing space 23.

In this connection, the auxiliary stand for assemblage may have astructure combined with those described above depending on the shape andthe procedures for assemblage of the device and the shape thereof canfurther be modified. Materials for the auxiliary stand for assemblageare not restricted to any specific one insofar as they are those capableof being shaped and/or processed, such as paper, metals, wood andplastic films (such as polypropylene, Teflon and polyvinyl chloridefilms), but preferred are plastic films having a high shape-retentionability and a thickness of not less than 0.5 mm.

FIG. 11 is a diagram showing the configuration of an iontophoresisdevice, in which the integrated electrode portion Ib-1 is incorporated,according to the present invention, after the completion of itsassemblage, wherein (a) and (b) are a view of the surface and a view ofthe back face of the device, respectively. As will be seen from thisfigure, a current-generating portion Ia is disposed on the surface ofthe electrode portion and a conductive snap connector Id is disposed onthe back face thereof. Thus, the electrode portion is fixed to andsandwiched between the current-generating portion Ia and the conductivesnap connector Id.

FIG. 12 is a diagram showing the configuration of an iontophoresisdevice, in which the separate type electrode portion Ib-2 isincorporated, according to the present invention, after the completionof its assemblage, wherein (a) and (b) are a view of the surface and aview of the back face of the device, respectively. In this embodiment, acurrent-generating portion Ia is disposed on the surface of the wiringsconnected to the electrode portion, while a conductive snap connector Idis arranged on the back face thereof. Thus, the wirings are fixed to andsandwiched between the current-generating portion Ia and the conductivesnap connector Id.

FIG. 13 is a diagram showing an embodiment, in which thecurrent-generating portion Ia is connected to the electrode portionthrough a connecting line 30, wherein (a), (b) and (c) are a connectingcord, having a fourth alignment structure and a view of the surface anda view of the back face of the device, respectively. In case of thisembodiment, a cord-connecting portion 31 (on the side of the electrodeportion), as the fourth alignment structure which is connected to oneend of the connecting cord, is arranged on the surface of the device anda conductive snap connector Id is arranged on the back face of thedevice. Thus, the electrode portion is fixed to the device by thecord-connecting portion 31 (on the side of the electrode portion) andthe conductive snap connector. A cord-connecting portion 32 (on the sideof the current-generating portion) is disposed on the other end of theconnecting line 30 and thus the cord-connecting portion is connected tothe current-generating portion. The cord-connecting portion 32 (on thecurrent-generating portion side) is equipped with an electrode terminal2′. The use of this connecting cord permits the operations of thisdevice at a place distant apart from the device.

Now, we will hereunder explain Examples of the method of assembling theiontophoresis device using these component parts.

EXAMPLE 1

FIG. 14 is a diagram illustrating an embodiment of the method ofassembling an iontophoresis device, which makes use of an integratedelectrode, in which (a) shows assembling processes and (b) shows aprocess in which the auxiliary stand Ie-4 for assemblage is used.

As shown in FIG. 14 (a){circumflex over (1)}, a cover material 9 of anintegrated electrode portion is first peeled off to thus expose adrug-dissolving portion 11. Then a current-generating portion Ia, a drugportion Ic and the integrated electrode portion Ib-1, which areindependent and separated from one another, are put in order using aconductive snap connector Id so that the integrated electrode and thedrug portion are in line with each other and arranged and in contactwith each other, as shown in FIG. 14(a){circumflex over (2)}. Next, aliner 17 of the drug portion on the electrode portion side (which hasbeen folded along a perforation) is peeled off as shown in FIG.14(a){circumflex over (3)}. Subsequently, a drug support 14 of the drugportion is connected to the drug-dissolving portion 11 of the integratedelectrode portion as shown in FIG. 14(a){circumflex over (4)}. Thus themoisture present in the drug-dissolving portion 11 penetrates into thedrug support 14 so that the drug is dissolved and activated. Thereafter,a liner 12 of the drug portion on the skin side is pulled out from theconductive snap connector Id as shown in FIG. 14(a){circumflex over(5)}. Further a liner 8 for an adhesive film is peeled off as shown inFIG. 14(a){circumflex over (6)}. At this stage, the device can beapplied to an affected part of a patient to thus initiate the treatmentthereof. In this regard, the liner 12 of the drug portion on theskinside is provided with a perforation 16 for pulling out the samethrough insertion openings 15 (two portions) for the conductive snapconnector as shown in FIG. 2 and accordingly, the liner can easily bepulled out.

In this Example, the device can likewise be assembled using theauxiliary stand Ie-4 for assemblage as shown in FIG. 14(b). Theiontophoresis device according to this Example permits the improvementof the long-term stability of a drug and easy and precise operations forassemblage. Thus the device permits the elimination of any artificialerror as much as possible and the supply of water required for thedissolution of the drug to the drug support in high precision. Moreover,the conductive snap connector simultaneously serves as a means foraligning the electrode portion and the drug portion and a means forelectrically connecting the electrode portion to the current generatingportion and therefore, the device can easily be applied to anyapplication site of a patient after the assemblage thereof.

EXAMPLE 2

FIG. 15 is a diagram illustrating another embodiment of the method ofassembling an iontophoresis device, which makes use of an integratedelectrode, in which (a) shows the first half of the assembling processand (b) shows the second half of the process, respectively.

An electrode portion is positioned using an alignment rod 20 of anauxiliary stand Ie-1 for assemblage as shown by an arrow {circumflexover (1)} in FIG. 15(a) and then a cover material 9 of the electrodeportion Ib-1 is peeled off as indicated by an arrow {circumflex over(2)} in FIG. 15(a) to thus expose a drug-dissolving portion 11. Then adrug portion Ic and the electrode portion Ib-1 are arranged and incontact with one another using the alignment rod 20 while they are inline with each other, as indicated by an arrow {circumflex over (3)} inFIG. 15(a). Subsequently, a liner 17 of the drug portion Ic on theelectrode portion side (which has been folded along a perforation) ispeeled off as indicated by an arrow {circumflex over (4)} FIG. 15(a),whereby a drug support 14 of the drug portion can easily be connected tothe drug-dissolving portion 11 of the integrated electrode portion asindicated by an arrow {circumflex over (5)} in FIG. 15(a). The moisturepresent in the drug-dissolving portion 11 penetrates into the drugsupport 14 and thus the drug is dissolved and activated. Thereafter, thepharmaceutical preparation is detached from the auxiliary stand asindicated by an arrow {circumflex over (6)} in FIG. 15(a).

Then a conductive snap connector Id and a current-generating portion Iaare disposed in the same configuration used in Example 1 as indicated byan arrow {circumflex over (7)} in FIG. 15(b). After pulling out a liner12 of the drug portion on the skin side immediately before theapplication of the device to the skin as indicated by an arrow{circumflex over (8)} in FIG. 15(b), a liner 8 for an adhesive film ispeeled off as shown by an arrow {circle around (9)} in FIG. 15(b). Atthis stage, the device can be fitted to an application site of a patientto thus initiate the treatment. The iontophoresis device according tothis Example makes the assemblage thereof upon application easier andmore accurate and therefore, it permits the elimination of anyartificial error as much as possible and the supply of water requiredfor the dissolution of the drug to the drug support in high precision.

EXAMPLE 3

FIG. 16 is a diagram illustrating a further embodiment of the method ofassembling an iontophoresis device, which makes use of an integratedelectrode, in which (a) shows the first half of the assembling processand (b) shows the second half of the process, respectively.

A current-generating portion Ia is incorporated into a space 23 foraccommodating the current-generating portion on an auxiliary stand Ie-2for assemblage so that an electrode terminal 2 (female) looks upward asindicated by an arrow {circumflex over (1)} in FIG. 16(a) and fixed tothe stand by means 22 for fixing. Then an electrode portion Ib-1 isdisposed while it coincides with a recess of the auxiliary stand Ie-2 asindicated by an arrow {circumflex over (2)} in FIG. 16(a) and thereaftera cover material 9 of the electrode portion Ib-1 is peeled off to thusexpose a drug-dissolving portion 11 as indicated by an arrow {circumflexover (3)} in FIG. 16(a). Subsequently, the electrode portion Ib-1 isbrought into contact with a drug portion Ic using a conductive snapconnector Id as indicated by arrows {circumflex over (4)} and{circumflex over (5)} in FIG. 16(a) in such a manner that they are inline with each other and thereafter a liner 17 of the drug portion Ic onthe electrode portion side (which has been folded along a perforation)is peeled off as indicated by an arrow {circumflex over (6)} in FIG.16(a). Then a drug support 14 of the drug portion is connected to thedrug-dissolving portion 11 of the integrated electrode portion as shownby an arrow {circumflex over (7)} in FIG. 16(a), whereby the moisturepresent in the drug-dissolving portion 11 penetrates into the drugsupport 14 and the drug is thus dissolved.

Thereafter a liner 12 of the drug portion on the skin side is pulled outfrom the conductive snap connector Id as indicated by an arrow{circumflex over (8)} in FIG. 16(b), then a liner 8 for an adhesive filmis peeled off immediately before the application of the device asindicated by an arrow {circumflex over (9)} in FIG. 16(b) and finallythe device is detached from the auxiliary stand. Thus, the iontophoresisdevice can be applied to an application site without any pre-treatmentto thus initiate the treatment. The iontophoresis device according tothis Example makes the assemblage thereof upon application easier andmore accurate and therefore, it permits the elimination of anyartificial error as much as possible and the supply of water requiredfor the dissolution of the drug to the drug support in high precision.

EXAMPLE 4

FIG. 17 is a diagram illustrating an embodiment of the method ofassembling an iontophoresis device, which makes use of a separate typeelectrode, in which (a) shows the first half of the assembling processand (b) shows the second half of the process, respectively.

First of all, a current-generating portion Ia is incorporated into aspace 23 for accommodating the current-generating portion on anauxiliary stand Ie-2 for activation in such a manner that two electrodeterminals (male) look upward, as indicated by an arrow {circumflex over(1)} in FIG. 17(a). Then the current-generating portion Ia is fixed tothe auxiliary stand Ie-2 by a fixing means 22 as shown by an arrow{circumflex over (2)} in FIG. 17(a). Next, electrode portions Ib-2(anode and cathode portions) are disposed on the auxiliary stand Ie-2such that each of the portions coincides with a recess on the stand.Thereafter, a cover material 9 on the electrode portion is peeled off tothus expose a drug-dissolving portion 11, as indicated by an arrow{circumflex over (3)} in FIG. 17(a). The cover material 9 of theelectrode portion can be peeled off after a drug portion and theelectrode portion are put on top each other, on the auxiliary stand.Subsequently, the electrode portion Ib-2 is brought into contact withthe drug portion Ic using a conductive snap connector Id in such amanner that these portions are in line with each other, as indicated byarrows {circumflex over (4)} and {circumflex over (5)} in FIG. 17(a) andthen a liner 17 of the drug portion on the electrode portion side (whichhas been folded along a perforation) is peeled off as indicated by anarrow {circumflex over (6)} in FIG. 17(a). Then a drug support 14 of thedrug portion is connected to the drug-dissolving portion 11 of theseparate type electrode portion as shown by an arrow {circumflex over(7)} in FIG. 17(a). As a result, the moisture present in thedrug-dissolving position 11 penetrates into the drug support 14 and thedrug therein is dissolved and activated.

Then a liner 12 of the drug portion on the skin side is pulled out fromthe conductive snap connector as shown by an arrow {circumflex over (8)}in FIG. 17(b) and thereafter, a liner 8 for an adhesive film is peeledoff immediately before the application of the device, as shown by anarrow {circumflex over (9)} in this figure. Finally, the device isremoved from the auxiliary stand. At this stage, the device can befitted to an application site to thus initiate a treatment.

In this respect, the order of the procedures for assembling the deviceis not restricted to that described above and may be hanged depending onthe mode of usage thereof by a patient, while taking measures suited tothe occasion. For instance, the device may have a structure in which abonding function is imparted to the cover material 9 of the electrodeportion and the cover material is peeled off and pulled out. Moreover,it is also possible that the device is not removed from the auxiliarystand, while the latter is used as an auxiliary means for fitting thedevice to an application site and then the stand is removed from thedevice after the completion of the application. As has been discussedabove, the iontophoresis device according to this Example permits, at atime, the achievement of the integration of the electrode portion (anodeand cathode portions), precision of activation (positioning) andoperability after the activation (easy handling ability) by the use ofthe conductive snap connector and the current-generating portion.Accordingly, the device can sufficiently show the desired functions.Moreover, the electrode portion can separately and independently beproduced and therefore, the separate type electrode portion is superiorto the integrated electrode portion in production facilities and qualitycontrol.

COMPARATIVE EXAMPLE 1

FIG. 18 is a schematic diagram showing an iontophoresis device as acomparative example, in which (a), (b) and (c) are a view of thesurface, views of the inner portion and back face and a cross sectionalview of the device, respectively. This Comparative Example relates to adevice in which an electrode portion and a drug portion are unifiedthrough a backing and is designed in such a manner that the electrodeportion and the drug portion connected through a hinge are folded at thehinged portion upon application after removing a liner 17 on theelectrode portion side to thus assemble the device. In this connection,internal structures of every portions are the same as those discussedabove in connection with Examples.

TEST EXAMPLE 1

Determination of Blood Concentration of Salmon Calcitonin

In this Example, the following are newly produced and used in respect ofExample 1 and Comparative Example 1: In Example 1 and ComparativeExample 1, 1.0 g of a 1.5% agar gel containing a citric acid bufferingsolution (33 mM, pH 5) was introduced into the conductive layer adjacentto 2.5 cm² of a silver-printed portion (anode), while 1.0 g of sodiumchloride-containing polyvinyl alcohol (UF-250G available from UnitikaLtd.) was introduced into a silver chloride-printed portion (cathode) toform an electrode portion. Moreover, a drug portion was prepared bydropwise addition of 20 IU of salmon calcitonin to 3.46 cm² of a drugsupport film (BIODYNE+ available from Nihon PALL Ltd.) and then dryingthe film.

After assembling the iontophoresis devices provided with the parts thusproduced, according to the procedures used in Example 1 and ComparativeExample 1, each device was fitted to the abdominal region of an SD rat(body weight: 250 g) and the device was electrically charged by passingan electric current from the current-generating portion at a pulsed,depolarized voltage of 12 V, through a donor electrode as an anode and areference electrode as a cathode. In this connection, four male personseach assembled the iontophoresis devices of Example 1 and ComparativeExample 1. Sera were obtained by intrajugularly collecting blood fromthe rats with the elapse of time. The concentration of salmon calcitoninin the sera were determined using a radio immunoassay kit (PeninsulaSalmon Calcitonin Quantitative Analysis Kit). The results thus obtainedare plotted on FIG. 19.

As will be seen from the results shown in FIG. 19, the bloodconcentrations of salmon calcitonin observed after 5 minutes were foundto be 2056±139 pg/ml (averaged value± standard deviation) for Example 1and 1867±548 pg/ml, the tendency of the changes in the bloodconcentration observed for Example 1 and Comparative Example 1 wereapproximately identical to each other and there was not observed anysignificant difference therebetween. However, the blood concentration ofsalmon calcitonin observed for Comparative Example 1 varied widely ascompared with that observed for Example 1 and this clearly indicatesthat the artificial errors upon the assemblage of the devices exertconsiderable influence on the blood concentration of salmon calcitonin.Consequently, these results clearly indicate that the assembling methodof Example 1 makes the assembling operations easy and precise whenpractically using the device and permits the elimination of anyartificial error as much as possible and the precise supply of waterrequired for the dissolution of the drug to the drug support.

TEST EXAMPLE 2

Evaluation of Stability with Time of Salmon Calcitonin Incorporated intoDrug Portion

The devices of Example 1 and Comparative Example 1 used in Test Example1 were packaged under the conditions specified in the following Table 1and allowed to stand at 25° C., 65% RH to thus evaluate the stability,with time, of salmon calcitonin.

TABLE 1 Structure of Drying Conditions for the Content Agent Allowing toStand Example 1 Drug portion alone Present 25° C., 65% RH ComparativeProvided with Present 25° C., 65% RH Example 1-A integrated electrodeand drug portions Comparative Provided with Absent 25° C., 65% RHExample 1-B integrated electrode and drug portions

In this Test Example, a composite aluminum packaging material (availablefrom OKADA SHIGYO K.K.) and 1.0 g of a product (available from OZOChemical Co., Ltd.) were used as the packaging material and the dryingagent, respectively. The results thus obtained are plotted on FIG. 20.

The results plotted on FIG. 20 indicate that, when the water-containingelectrode portion and the drug portion in a dried condition are packedin the same package, the former adversely affects the stability, withtime, of the drug in the drug portion. In addition, when the electrodeand drug portions are packed in the same package and a drying agent isused therein, the drug stability is improved to some extent, but it wasfound, in one out of four cases, that the water in the electrode portionwas exhausted after allowing it to stand over 6 months. On the otherhand, the drug exhibited quite excellent stability in the device ofExample 1.

From the foregoing, it would be recognized that it is practicallydifficult to ensure the long-term stability of a drug using a deviceprovided with integrated electrode and drug portions. Moreover, in caseof a device provided with electrode and drug portions separated from oneanother, a drying agent may be used and therefore, the long-termstability of a drug would further be improved.

In addition, the iontophoresis device according to the present inventionhas technical features described above and therefore, the threeportions, i.e., the current-generating portion the drug portion andelectrode portion can separately be stored before the operation of thedevice. For this reason, if a drug having insufficient stability towater (such as physiologically active peptides) is incorporated into thedrug portion, it is not feared that the drug is decomposed with time dueto the evaporation of water present in the electrode portion providedwith the built-in drug-dissolving portion.

Moreover, the device does not require any package for the completeelimination of the evaporation of water originated from the electrodeportion and therefore, the device is also advantageous from theeconomical standpoint. Furthermore, an agent for improving the stabilityof the drug portion such as drying agent can be used in the deviceaccording to the present invention while such an agent cannot be used incase where the drug portion and the electrode portion are united,because of the influence thereof on the drug-dissolving portion andaccordingly, the long-term stability of the drug is further improved.

Moreover, the device of the present invention is designed in such amanner that the drug support of the drug portion automatically contactswith the drug-dissolving portion of the electrode portion and the drugpresent in the drug support is thus activated, by assembling, uponoperating the device, the separately stored three portions, i.e., thecurrent-generating portion, the drug portion and the electrode portionwith the aid of the conductive snap connector or the auxiliary stand forassemblage such that there is no aberration of position between theelectrode and drug portions and by peeling off and pulling out the linerof the drug portion from the device. For this reason, the presentinvention makes the assembling operations easy and precise whenpractically using the device and permits the elimination of anyartificial error as much as possible and the precise supply of waterrequired for the dissolution of the drug to the drug support.

In addition, the conductive snap connector also serves as a means forelectrically connecting the electrode portion to the current-generatingportion and therefore, the treatment of a patient can be initiatedsimply by fitting the device, after the assemblage, to an applicationsite of the patient. The operability of the device would be furtherimproved if using an auxiliary stand for assemblage as a means forhelping the application of the device.

From the foregoing, the iontophoresis device according to the presentinvention exhibits excellent pharmacological effect and permits theachievement of an improved compliance of patients. Moreover, the devicecan ensure sufficient safety in both operations and functions and thushas high reliability.

Industrial Applicability

The iontophoresis device according to the present invention is effectivefor ensuring the long-term stability of a drug and the method ofassembling the device according to the present invention is advantageousin that the device can easily be assembled. Therefore, the presentinvention is suitably used for the iontophoresis in the medical field.

What is claimed is:
 1. An iontophoresis device comprising adrug-dissolving portion provided with an electrode portion having afirst alignment structure and a drug support provided with a drugportion having a second alignment structure, which coincides with thefirst alignment structure, wherein the drug support contacts with thedrug-dissolving portion by coinciding the second alignment structure ofthe drug portion with the first alignment structure of the electrodeportion.
 2. The iontophoresis device according to claim 1, wherein thefirst and second alignment structures are openings formed on theelectrode portion and the drug portion, respectively.
 3. Theiontophoresis device according to claim 1, further comprising acurrent-generating portion connected to a connecting cord having afourth alignment structure, which coincides with the first alignmentstructure of the electrode portion, wherein the connecting cord iscoupled to the electrode portion by coinciding the fourth alignmentstructure of the connecting cord with the first alignment structure ofthe electrode portion.
 4. The iontophoresis device according to claim 1,further comprising a current-generating portion having a third alignmentstructure, which coincides with the first alignment structure of theelectrode portion, wherein the current-generating portion is coupled tothe electrode portion by coinciding the third alignment structure of thecurrent-generating portion with the first alignment structure of theelectrode portion.
 5. The iontophoresis device according to claim 4,wherein the third alignment structure is an electrode terminal formed onthe current-generating portion.
 6. An iontophoresis device comprising adrug-dissolving portion provided with an electrode portion having afirst alignment structure, a current-generating portion having a thirdalignment structure, which coincides with the first alignment structureand a connector having a fifth alignment structure, which coincides withthe first alignment structure, wherein the electrode portion, thecurrent-generating portion and the connector are coupled together whilethe electrode portion is sandwiched between the current-generatingportion and the connector by coinciding the said alignment structureswith each other.
 7. The iontophoresis device according to claim 6,wherein the alignment structures are constituted by a conductivematerial.
 8. An iontophoresis device comprising a current-generatingportion for supplying a driving force for drug-absorption, a drugportion provided with a drug support and an electrode portion providedwith a drug-dissolving portion, wherein the electrode portion and thedrug portion are arranged while they are in contact and in line with oneanother by the use of a means for maintaining the arrangement uponoperation of the device to thus contact the drug support of the drugportion with the drug-dissolving portion of the electrode portion. 9.The iontophoresis device according to claim 8, wherein at least the drugportion among the current-generating portion, the electrode portion andthe drug portion is packed in a separate package.
 10. The iontophoresisdevice as set forth in claim 8, wherein the arrangement-maintainingmeans serves to mechanically connect the electrode portion to the drugportion and/or to electrically connect the electrode portion to thecurrent-generating portion.
 11. The iontophoresis device according toclaim 8 wherein the arrangement-maintaining means includes at least oneof a current-generating portion, a conductive snap connector and anauxiliary stand for assemblage.
 12. An iontophoresis device set at leastcomprising an electrode portion having a first alignment structure and adrug-dissolving portion; and a drug portion having a second alignmentstructure, which coincides with the first alignment structure, and adrug support, wherein the drug portion and the electrode portion areseparately accommodated.
 13. The iontophoresis device set according toclaim 12, further comprising a current-generating portion having a thirdalignment structure, which coincides with the first alignment structureand a connector having a fifth alignment structure, which coincides withthe first alignment structure, wherein the drug portion is accommodatedindependent of the current-generating portion and the connector.
 14. Theiontophoresis device set according to claim 12, further comprising anauxiliary stand for assemblage having a sixth alignment structure, whichcoincides with the first alignment structure, wherein the drug portionand the auxiliary stand are separately accommodated.
 15. A method ofassembling an iontophoresis device, which comprises an electrode portionhaving an alignment structure and a drug-dissolving portion covered witha cover material; and a drug portion having an alignment structure and adrug support whose both sides are covered with covers, comprising thesteps of peeling off the cover material of the electrode portion;coinciding the alignment structures of the electrode and drug portionswith each other to thus put the drug support of the drug portion inposition on the drug-dissolving portion of the electrode portion;peeling off the cover of the drug support on the side of thedrug-dissolving portion; and fixing the drug support to the electrodeportion.
 16. The method of assembling an iontophoresis device accordingto claim 15, further comprising a step of peeling off at least part ofthe cover of the drug support on the side opposite to thedrug-dissolving portion.
 17. The method of assembling an iontophoresisdevice according to claim 16, wherein the device is also provided withan auxiliary stand for assemblage having an alignment structure and thealignment structures of the electrode and drug portions coincide witheach other using the alignment structure of the auxiliary stand forassemblage.
 18. The method of assembling an iontophoresis deviceaccording to claim 17, wherein both of the alignment structures of theelectrode and drug portions are openings formed on the electrodeportion, and the drug portion respectively, and the alignment structureof the auxiliary stand for assemblage is an alignment rod capable ofbeing inserted into the openings.
 19. The method of assembling aniontophoresis device according to claim 16, wherein the device isprovided with a current-generating portion having an alignment structureand an auxiliary stand for assemblage having an alignment structure andthe alignment structures of the electrode and drug portions coincidewith each other using the alignment structures of the auxiliary standfor assemblage and the current-generating portion.
 20. The method ofassembling an iontophoresis device according to claim 19, wherein bothof the alignment structures of the electrode and drug portions areopenings formed on the electrode and drug portions respectively, thealignment structure of the auxiliary stand for assemblage is a space foraccommodating the current-generating portion and the alignment structureof the current-generating portion is an electrode terminal capable ofbeing inserted into the openings.
 21. The method of assembling aniontophoresis device according to claim 16, wherein the device isprovided with a current-generating portion having an alignmentstructure, an auxiliary stand for assemblage having an alignmentstructure and a connector having an alignment structure; the alignmentstructures of the electrode and drug portions coincide with one anotherusing the three alignment structures of the auxiliary stand forassemblage, the current-generating portion and the connector.
 22. Themethod of assembling an iontophoresis device according to claim 21,wherein both of the alignment structures of the electrode and drugportions are openings formed on the electrode and drug portionsrespectively, the alignment structure of the auxiliary stand forassemblage is a space for accommodating the connector and the alignmentstructure of the connector is a connecting member capable of being fixedto the alignment structure of the current-generating portion through theopenings of the electrode and drug portions.
 23. The method ofassembling an iontophoresis device according to claim 15, wherein thedevice is also provided with an auxiliary stand for assemblage having analignment structure and the alignment structures of the electrode anddrug portions coincide with each other using the alignment structure ofthe auxiliary stand for assemblage.
 24. The method of assembling aniontophoresis device according to claim 23, wherein the both of thealignment structures of the electrode and drug portions are openingsformed on the electrode portion and the drug portion respectively andthe alignment structure of the auxiliary stand for assemblage is analignment rod capable of being inserted into the openings.
 25. Themethod of assembling an iontophoresis device according to claim 15,wherein the device is provided with a current-generating portion havingan alignment structure and an auxiliary stand for assemblage having analignment structure and the alignment structures of the electrode anddrug portions coincide with each other using the alignment structure ofthe auxiliary stand for assemblage and the current-generating portion.26. The method of assembling an iontophoresis device according to claim25, wherein the both of the alignment structures of the electrode anddrug portions are openings formed on the electrode and drug portionsrespectively, the alignment structure, of the auxiliary stand forassemblage is a space for accommodating the current-generating portionand the alignment structure of the current-generating portion is anelectrode terminal capable of being inserted into the openings.
 27. Themethod of assembling an iontophoresis device according to claim 15,wherein the device is provided with a current-generating portion havingan alignment structure, an auxiliary stand for assemblage having analignment structure and a connector having an alignment structure; thealignment structures of the electrode and drug portions coincide withone another using the three alignment structures of the auxiliary standfor assemblage, the current-generating portion and the connector. 28.The method of assembling an iontophoresis device according to claim 27,wherein the both of the alignment structures of the electrode and drugportions are openings formed on the electrode and drug portionsrespectively, the alignment structure of the auxiliary stand forassemblage is a space for accommodating the connector and the alignmentstructure of the connector is a connecting member capable of being fixedto the alignment structure of the current-generating portion through theopenings of the electrode and drug portions.
 29. A method of assemblingan iontophoresis device comprising the step of coinciding an alignmentstructure of an electrode portion with an alignment structure of a drugportion using at least one of alignment structures of an auxiliary standfor assemblage, a current-generating portion and a connector to thus puta drug support of the drug portion in position on a drug-dissolvingportion of the electrode portion.
 30. The method of assembling aniontophoresis device according to claim 29, wherein the both alignmentstructures of the electrode and drug portions are openings formed on theelectrode and drug portions respectively and at least one of thealignment structures of the auxiliary stand for assemblage, thecurrent-generating portion and the connector is a rod-like membercapable of being inserted into the openings.